Methods for Delivering Volatile Anesthetics for Regional Anesthesia and/or Pain Relief

ABSTRACT

The present invention provides methods for reducing pain in a subject in need of such pain reduction by delivering, e.g., intrathecally or epidurally, a volatile anesthetic such as a halogenated ether compound in an amount effective to reduce pain. Chronic or acute pain may be treated, or the anesthetic may be delivered to the subject to anesthetize the subject prior to a surgery. In certain embodiments, isoflurane, halothane, enflurane, sevoflurane, desflurane, methoxyflurane, xenon, and mixtures thereof may be used. Dosing regimens including a one-time administration, continuous and/or periodic administration are contemplated.

This application claims priority to U.S. Provisional Application No.60/846,293 filed on Sep. 20, 2006, and U.S. Provisional Application No.60/947,219 filed on Jun. 29, 2007, the entire disclosures of which arespecifically incorporated herein by reference in their entirety withoutdisclaimer.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the fields of anesthesia andpain management. More specifically, the present invention providesmethods for reducing pain by regionally delivering a solution comprisinga volatile anesthetic to a subject in need of pain reduction oranesthesia.

2. Description of Related Art

Millions of people suffer from pain. The pain may be minor, such asheadaches, acute lower back pain, and acute muscle pain, or severe, suchas chronic pain. Chronic pain may be associated with cancer treatment,HIV, diabetes, or other conditions. Chronic pain can be difficult totreat, with many chronic pain sufferers noting that their pain is notwell controlled with current pain medications or that their medicationshave significant associated adverse effects (e.g., nausea and vomiting,dependence, tolerance, etc.).

In an attempt to address the problem of chronic pain management,intrathecal infusion pumps and neurostimulators have been developed.Intrathecal infusion pumps are aimed at continuous, or near continuousdelivery of liquid anesthetic and/or analgesic agents. Many of theseinfusion pumps are totally implantable, which helps to reduce the riskof infection when compared to the long-term use of external systems. Theinfusion pump may also be programmable to allow patients or theirclinicians to adjust dosing amounts or daily delivery schedule, helpingto meet a patient's changing needs.

Neurostimulators are available in various forms and stimulate nerves torelieve pain. Both intrathecal pumps and neurostimulators havedrawbacks, including the onset of tolerance, with the treatmentsbecoming less effective over time. In addition, neither intrathecalinfusion pumps nor neurostimulators are suitable for anesthetizing apatient prior to a surgery.

Various approaches for inducing anesthesia or analgesia are known.Delivery of a general anesthetic renders a patient unconscious andunaware of the surgery. In contrast, anesthetics may be appliedregionally, for example, to the spine, epidurally, or near a nerve in anerve block to anesthetize only a portion of the patient's body. Forgeneral anesthesia, delivery of a general anesthetic to a patient priorto surgery is typically performed using an initial i.v. injection of ananesthetic followed by intubation and administration of an inhalableanesthetic gas. It is worthwhile to note that the mechanism of actionfor general anesthesia is still not completely understood.

Considerable negative side effects may result from administration ofgeneral anesthesia. A large tube has to be placed into the trachea,which can result in trauma to the upper airway. Many patients reportpostoperative hoarseness and tenderness of the mouth and throat. Inaddition, the large amount of gases required to flood the body to reachthe targeted organs can have an adverse affect on the non-targetedorgans, especially the heart, with an increased risk of cardiopulmonarymorbidity during general anesthesia. Especially in the elderly, there issubstantial evidence for prolonged cognitive dysfunction followinggeneral anesthesia (Moller et al., 1998). Additionally, regionalanesthetic techniques appear to lead to less overall morbidity andmortality from cardiopulmonary causes as compared to general anesthesia(Rasmussen et al., 2003; Rogers et al., 2000)

Clearly, there exists a need for improved methods for pain managementand regional anesthesia. Further, there exists a need for additionalmethods for delivering an anesthetic, such as a halogenated ether or avolatile anesthetic, for treating pain or for use in a surgicalprocedure.

SUMMARY OF THE INVENTION

The present invention overcomes limitations in the prior art byproviding new methods for administering anesthetics and reducing pain ina subject, such as a human or animal patient or laboratory animal suchas a mouse or rat, in need of such pain reduction. The methodspreferably comprise the local or regional delivery, such as intrathecalor epidural delivery, of a volatile anesthetic in an aqueous basedsolution to the subject in an amount effective to reduce chronic oracute pain. In certain embodiments, and the anesthetic may be deliveredto the subject to anesthetize the subject prior to a surgery. It shouldbe understood, that as used herein, the phrase “pain reduction” isintended to cover pain reduction as a result of anesthesia, analgesia,and/or the inhibition of neural impulses involved in pain perception,e.g., via partial nerve conduction block.

The present invention has several substantial advantages over previouslyused methods for regional anesthesia. These advantages include: (1) thevolatile anesthetics of the present invention are rapidly titratable,thus administration of a volatile anesthetic according to the presentinvention can result in a very quick onset of analgesia or regionalanesthesia. (2) The present invention allows for the quick dissipationof anesthetics after administration; thus the anesthesia or analgesiamay be rapidly ended. These properties are of particular value to apractitioner, as it may be desirable for a practitioner to quickly alterthe dosing of a regional anesthesia or analgesia as desired. (3) Certaindrugs presently used for regional anesthesia may not be effectively usedon various individuals for a variety of reasons, including tolerance,drug interactions, paradoxical responses, etc. Additionally, (4) thevolatile anesthetics of the present invention are generally non-opioidcompounds, which provides various benefits for a practitioner, asopioids possess certain disadvantages, including tolerance, druginteractions, and dependence etc.

An aspect of the present invention relates to a method for reducing painin a subject in need of such pain reduction comprising regionally orlocally delivering to the subject a volatile anesthetic dissolved in asolution in an amount effective to reduce pain. In preferredembodiments, the anesthetic is delivered by routes other thanintravenously in that intravenous delivery could potentially give riseto general anesthesia that, while not specifically excluded from thepresent invention, is not a preferred aspect. Preferred volatileanesthetics are the halogenated ether anesthetic dissolved in anaqueous, pharmaceutically acceptable solution. The anesthetic maypreferably be delivered intrathecally, epidurally, or in a nerve blockprocedure, to relieve, for example, chronic pain or acute pain.

In certain embodiments, a volatile anesthetic in solution is deliveredto anesthetize a portion of the subject prior to a surgery. In preferredembodiments, the volatile anesthetic is a halogenated volatileanesthetic selected from the group consisting of isoflurane, halothane,enflurane, sevoflurane, desflurane, methoxyflurane, and mixturesthereof, with isoflurane being particularly preferred. The solution,such as an isoflurane solution, may be prepared in a concentration ofabout 5 ng/ml solution to about 100 ng/ml solution. The solution maycomprise from about 5% to about 75% v/v, from about 10% to about 50%v/v, or about 10% v/v anesthetic in solution. The anesthetic may beisoflurane and/or the solution may be artificial cerebrospinal fluid.When administered epidurally or intrathecally it is desirable to achievea concentration of from about 250 ng/ml to about 50,000 ng/ml of activeagent in the spinal fluid. The delivery of the active agent may becontinuous, periodic, a one-time event, or the active agent may be bothperiodically administered and continuously administered to the subjecton separate occasions. The reduction may comprise elimination of painperception of a portion of the body of the subject.

Preferably, in that the solution is intended for parenteraladministration, the aqueous solution comprising the volatile anestheticis sterile. This can be achieved by ensuring that all starting materialsare sterile and maintaining them under sterile conditions prior toadministration. As for the underlying aqueous solution, the nature ofthe solution is not believed to be critical, and solutions such asnormal saline or even solutions formulated to mimic natural body fluids,such as artificial cerebrospinal fluids, are contemplated. However, itis highly preferable to exclude oil-in-water emulsions, such as lipidemulsions, from inclusion in the solutions of the present invention.

Yet another aspect of the present invention involves a sealed containercomprising an anesthetic solution of the present invention. The interiorof the container may be sterile. The container may comprise a rubberstopper which can be easily pierced by an injection needle. Thecontainer may comprise the chamber portion of a syringe. The containermay comprise a drip chamber. The drip chamber may be coupled to acatheter. The catheter may be an epidural catheter or an intrathecalcatheter. The container may be a plastic bag, a glass bottle, or aplastic bottle. The container may be coupled to an infusion pump. Theinfusion pump may be an intrathecal pump, an epidural delivery infusionpump, or a patient control analgesia (PCA) pump. The infusion pump maybe programmable.

The terms “inhibiting,” “reducing,” or “prevention,” or any variation ofthese terms, when used in the claims and/or the specification includesany measurable decrease or complete inhibition to achieve a desiredresult.

The term “effective,” as that term is used in the specification and/orclaims, means adequate to accomplish a desired, expected, or intendedresult.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventioncan be used to achieve methods of the invention.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating specific embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: A flowchart representing a general method for delivering ananesthetic gas to a subject.

FIG. 2: Inhibition of pain via intrathecal administration of isofluranesolution as measured using the hotplate test.

FIG. 3: Inhibition of pain using intrathecal isoflurane in artificialcerebrospinal fluic (ACSF). The time course for paw withdrawal from ahotplate after administration of isoflurane-ACSF, at a dose of 1.46 mgisoflurane, is shown.

FIG. 4: A stimulus response (SR) graph is shown of the maximal possibleeffect (MPE) by dose for the time point of 10 minutes after intrathecalinjection of isoflurane-ACSF.

DETAILED DESCRIPTION

The present invention provides methods for reducing pain in a subject inneed of such pain reduction. Specifically, although volatile anestheticsare normally inhaled during a general anesthesia procedure, theinventors have discovered that volatile anesthetics may be dissolved ina solution and delivered regionally or locally (e.g., intrathecally,epidurally, or in a nerve block) to inhibit or block pain perception. Ingeneral, the methods may involve the delivery of a halogenated etheranesthetic to the subject in an amount effective to reduce pain. Thepresent invention may be used for pain management of chronic or acutepain. In other embodiments, the anesthetic may be delivered to a subjectto anesthetize at least a portion of the subject prior to a surgery.

Anesthetic Agents

In general, the halogenated ether anesthetics or volatile anestheticssuitable for use with the described methods include agents which,although often liquid at room temperature, are capable of easily beingbecoming gaseous or are already gaseous at room temperature and canreduce pain, e.g., without significant side effects. It may bedesirable, for example, to select an anesthetic that is minimallymetabolized by the body or is otherwise inert. In this way, liver andkidney toxicity may be minimized. Similarly, it may be desirable for theanesthetic to have a short half-life, or be fast acting to promotetitratability (i.e., the subject can easily adjust the delivery amountfor the amount of pain he or she is experiencing). An active agent gasthat does not produce tolerance (unlike opioids or local anestheticagents) or dependence (like opioids) may also be desirable.

Volatile anesthetics are a well known class of anesthetics whichincludes halogenated ether compounds, isoflurane, sevoflurane,halothane, enflurane, desflurane, methoxyflurane, and diethyl ethers. Incertain embodiments xenon may also be used with the present invention. Asingle anesthetic or mixtures of the above anesthetics may beparticularly suitable for use with the methods described herein.

In various embodiments, a gas anesthetic may used with the presentinvention. For example, the gas anesthetic may be dissolved in asolution according to the present invention and administered in aregional or local anesthesia procedure, such as an epidural,intrathecal, or nerve block procedure. Gas anesthetics other thanhalogenated anesthetics are contemplated, and examples or which includexenon, nitrous oxide, cyclopropane, and ether. In various embodiments,other biologically active gases (e.g., nitric oxide, etc.) may bedelivered in a solution to a subject according to the present invention.

More than one anesthetic may be administered at one time, and differentanesthetics may be administered at various times throughout a singletreatment cycle. For example, 2, 3, 4 or more anesthetic agents may besimultaneously or repeatedly administered to a subject. When compoundsare repeatedly administered to a subject, the duration betweenadministration of compounds may be about 1-60 seconds, 1-60 minutes,1-24 hours, 1-7 days, 1-6 weeks or more, or any range derivable therein.In some instances, it may be desirable to stage the delivery ofdifferent halogenated ether compounds depending on their physical andphysiological properties.

Dosing

The amount of the anesthetic to be administered, e.g., intrathecally orepidurally, depends on the particular indication desired. For example,the dose will depend on the type of pain intended to be treated. Thedose may be different, for instance, if the delivery of the anestheticis intended to reduce chronic pain as opposed to acute pain. Similarly,the dose may be different if the active agent will be used toanesthetize a subject (locally or generally). The subject's physicalcharacteristics may also be important in determining the appropriatedosage. Characteristics such as weight, age, and the like may beimportant factors. For example, the anesthetic may have increasedpotency with age, as has been demonstrated in the case of the volatileanesthetic isoflurane.

The temperature of the volatile anesthetic may also be considered as afactor in selecting an appropriate dose, as the solubility of manyanesthetics may be affected by the temperature of the anesthetic and/oraqueous solution. For example, increases in temperature may increase thesolubility, and thus potency, of the active agent; this property hasbeen demonstrated with certain anesthetic agents. The particular dosagemay also be dependent on the dosing regime chosen. For example, theactive agent may be delivered continuously or periodically. Conversely,the active agent may be administered as a single administration as aone-time event.

Volatile anesthetics (e.g., halogenated anesthetic compounds) may beinfused in amounts leading to spinal fluid levels in the range of about250 to about 50,000 nanograms/ml, depending on the anesthetic selectedand the desired effect. In certain embodiments, a halogenated anestheticor volatile anesthetic may be administered to achieve cerebrospinalfluid (CSF) concentration of from about 5 to about 500,000 nanograms/ml.While the dose range will vary depending on the compound selected andpatient variability, it is generally true that lower doses such as fromabout 0.01 to about 10,000 nanogram/ml are more suitable for treatingminor to moderate pain, while higher doses such as from about 10000nanogram/ml to about 500,000 nanogram/ml or more are suitable fortreating severe pain and inducing anesthesia. Of course, the doses maybe given once (for a minor single occurrence of pain), repeatedly (formoderate or chronic pain), or continuously (for severe pain oranesthesia purposes). Combinations of these dosing regimes may also beused. For example, a subject suffering from severe pain may requirecontinuous dosing with periodic additional dosing needed forbreakthrough pain.

In embodiments where an anesthetic (e.g., a volatile anesthetic,isoflurane, etc.) is admixed with a solution, such as saline or anartificial CSF solution, the concentration of the volatile anestheticmay vary. For example, a solution may contain an anesthetic in a v/vratio of from about 1 to about 99%, from about 10 to about 75%, fromabout 10 to about 50%, from about 20 to about 50%, about 50%, about 45%,about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about10%, about 5% or any range derivable therein. In these embodiments, theanesthetic may be a volatile anesthetic, such as isoflurane, and thesolution may be an artificial cerebrospinal fluid (ACSF) solution.

In various embodiments and as shown in the below examples, a solution ofabout 10% volatile anesthetic, such as isoflurane, may be used; thissolution may be administered as a bolus injection, continuously, and/orrepeatedly to achieve analgesia and/or anesthesia. Thus, as demonstratedin the below examples, a 10% v/v solution of a volatile anesthetic maybe used to induce analgesia. Higher concentrations of volatileanesthetic may be used, in various embodiments, to induce a regionalanesthesia.

Method of Active Agent Delivery

Anesthetics of the present invention may be delivered regionally orlocally. “Regional” or “local” anesthesia, as used herein, is distinctfrom general anesthesia and refers to anesthetic procedures which allowfor the preferential delivery of an anesthetic to a specific region ofthe body, such as near a nerve or a nerve bundle. In contrast, generalanesthesia allows for the systemic administration of an anesthetic,e.g., via intravenous administration. Regional or local anesthesiatypically allows for a lower total body concentration (although elevatedlocal concentrations) of an anesthetic to be administered to a subjectfor analgesia or diminished pain perception of at least a portion of thesubject's body. For example, intrathecal anesthesia, epiduralanesthesia, and nerve blocks are examples of regional or localanesthesia. Specific concentrations of anesthetics which may be used forregional or local anesthesia include from about 250 to about 50,000nanogram/ml, from about 250 to about 25000 nanogram/ml, from about 250to about 10000 nanogram/ml, from about 250 to about 5000 nanogram/ml,from about 250 to about 2500 nanogram/ml, or from about 250 to about1000 nanogram/ml.

The present invention may be used with various nerve block procedures.Nerve block procedures according to the present invention may beperformed with or without ultrasound visualization; for example, anultrasound machine may be used to visualize the region of the bodyinvolved a the nerve block procedure, such as, e.g., various nervebundles in the shoulder, neck, lower back, etc. The inventors envisionthat the present invention may be used in conjunction with a hipreplacement, shoulder replacement, and/or birthing-related procedures.

In certain embodiments, compositions and methods of the presentinvention may be used for pain management. Pain management is distinctfrom general anesthesia in that a lower total body concentration of ananesthetic may be administered to a subject to in order to increaseanalgesia or decrease perception of pain, preferably without renderingthe subject unconscious. Specific concentrations of anesthetics whichmay be used for pain management include from about 250 to about 50,000nanogram/ml, from about 250 to about 25000 nanogram/ml, from about 250to about 10000 nanogram/ml, from about 250 to about 5000 nanogram/ml,from about 250 to about 2500 nanogram/ml, or from about 250 to about1000 nanogram/ml.

Epidural or intrathecal administration of an anesthetic may beaccomplished via techniques known in the art, such as the use of anintrathecal or epidural catheter. The catheter should be placed closerto the nerves critical for the propagation of any pain sensoryinformation which the practitioner desires to inhibit, without damagingthe nerves.

Other routes of administration which are contemplated include:injection, infusion, continuous infusion, localized perfusion bathingtarget cells directly, via a catheter, via nanoparticle delivery,topical administration (e.g., in a carrier vehicle, a topical controlrelease patch), intra-articular, intravenous and/or oral administration.An appropriate biological carrier or pharmaceutically acceptableexcipient may be used. Compounds administered may, in variousembodiments, be racemic, isomerically purified, or isomerically pure.

In certain embodiments, anesthetics of the present invention are notadministered intravenously. Intravenous administration is often used forgeneral anesthesia (Mathias et al., 2004) and typically results in therapid distribution of the anesthetic agent throughout the body of asubject. Thus, in certain embodiments, intravenous administration isincompatible for use with regional or local anesthesia.

FIG. 1 provides a flowchart depiction of a general method for deliveringa halogenated ether anesthetic. As shown in FIG. 1, method (100) beginswith the selection of an halogenated ether compound (102). Thehalogenated ether anesthetic may be a standard volatile anesthetic gas,or an active agent that is capable or reducing pain and of becomingreadily gaseous, as described above.

Solutions

After a halogenated ether anesthetic has been selected, it may bedissolved into a solution (104). The solution may be an aqueoussolution, such as saline, artificial cerebrospinal fluid, the subject'sown cerebrospinal fluid, or the like. In some variations, othersolutions may be appropriate.

Various formulations of saline are known in the art and may be used withthe present invention. For example, the saline may be lactated Ringer'ssolution, acetated Ringer's solution, phosphate buffered saline (PBS),Dulbecco's phosphate buffered saline (D-PBS), Tris-buffered saline(TBS), Hank's balanced salt solution (HBSS), or Standard saline citrate(SSC).

The saline solutions of the present invention are, in certainembodiments, “normal saline” (i.e., a solution of about 0.9% w/v ofNaCl). Normal saline has a slightly higher degree of osmolality comparedto blood; however, in various embodiments, the saline may be isotonic inthe body of a subject such as a human patient. Normal saline (NS) isoften used frequently in intravenous drips (IVs) for patients who cannottake fluids orally and have developed severe dehydration. In certainembodiments, “half-normal saline” (i.e., about 0.45% NaCl) or“quarter-normal saline” (i.e., about 0.22% NaCl) may be used with thepresent invention. Optionally, about 5% dextrose or about 4.5 g/dL ofglucose may be included in the saline. In various embodiments, one ormore salt, buffer, amino acid and/or antimicrobial agent may be includedin the saline.

Various artificial cerebrospinal fluid (ACSF) solutions may be used withthe present invention. In certain embodiments, the ACSF is a bufferedsalt solution (pH 7.4) with the following composition (in mM): NaCl,120; KCl, 3; NaHCO₃, 25; CaCl₂, 2.5; MgCl₂, 0.5; glucose, 12. ACSF canalso be obtained from various commercial sources, such as from HarvardApparatus (Holliston, Mass.).

In various embodiments, a preservative or stabilizer may be included inthe composition or solution. For example, the prevention of the actionof microorganisms can be brought about by preservatives such as variousantibacterial and antifungal agents, including but not limited toparabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol,sorbic acid, thimerosal or combinations thereof. Agents which may beincluded suitable for injectable use include sterile aqueous solutionsor dispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersions (U.S. Pat. No. 5,466,468,specifically incorporated herein by reference in its entirety). In allcases the composition is preferably sterile and must be fluid tofacilitate easy injectability. Solutions are preferably stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi.Examples of stabilizers which may be included include buffers, aminoacids such as glycine and lysine, carbohydrates such as dextrose,mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol,mannitol, etc. Appropriate stabilizers or preservatives may be selectedaccording to the route of administration desired.

The weight ranges of compounds in the solution may vary. For example, invarious embodiments, the composition may comprise about 1-5 wt %anesthetic agent, about 1-5 wt % preservative/stabilizer, about 1-5 wt %NaCl, and about 85%-97% water. The ratio of anesthetic to water may bevaried as needed to achieve the desired effect (pain reduction oranalgesia, regional anesthesia, etc.).

The solution and/or composition may also be sterilized prior toadministration. Methods for sterilization are well known in the art andinclude heating, boiling, pressurizing, filtering, exposure to asanitizing chemical (e.g., chlorination followed by dechlorination orremoval of chlorine from solution), aeration, autoclaving, and the like.

The active agent gas may be dissolved into the solution in any number ofways. For example, it may be bubbled through the solution, e.g., using avaporizer, or it may be solubilized by agitation. In certainembodiments, an anesthetic such as a halogenated ether or a volatileanesthetic may be measured in liquid form and directly admixed into asolution. Of course, other suitable methods of dissolving the anestheticinto solution may also be used. After the halogenated ether anesthetichas been solubilized, it may be administered to a subject in need ofpain reduction (including pain reduction in the form of anesthesia)epidurally or intrathecally (FIG. 1, 106) using techniques well known inthe art. In certain embodiments, a volatile anesthetic is admixed with asolution in a closed vacuum container, and the combined solutions arethen mechanically agitated for 3-5 minutes and held in a thermo-neutralsonicator until use.

In preferred embodiments, solutions of the present invention areessentially free of oil-in-water emulsions such as soybean emulsion.Oil-in-water emulsions may alter the pharmacokinetics and/ordistribution of an anesthetic, which may not be desirable in certaininstances. Additionally, in various embodiments, oil-in-water emulsionsare not desirable for intrathecal or epidural applications, as apractitioner may not wish to inject oil into the spinal canal. Saline,artificial CSF, or the patients own CSF may be used for intrathecal orepidural administration of an anesthetic according to the presentinvention. Lipid emulsions also have other drawbacks and risks. Forexample, depending on the route, lipid emulsions can cause pain andirritation upon injection. Lipid emulsions also pose a not insubstantialrisk of infection, as has been observed in the past with bacteriallycontaminated propofol emulsions. The present invention addresses theselimitations by providing solutions which can reduce pain perception uponinjection and may have a reduced risk of contamination.

Pharmaceutical compositions of the present invention comprise aneffective amount of one or more anesthetic or biologically active gas oradditional agent dissolved or dispersed in a pharmaceutically acceptablecarrier. The phrases “pharmaceutical or pharmacologically acceptable”refers to molecular entities and compositions that do not produce anadverse, allergic or other untoward reaction when administered to ananimal, such as, for example, a human, as appropriate. The preparationof an pharmaceutical composition that contains at least one anestheticor biologically active gas in solution or additional active ingredientwill be known to those of skill in the art in light of the presentdisclosure, as exemplified by Remington: The Science and Practice ofPharmacy, 20th Edition (2000), which is incorporated herein byreference. Moreover, for animal (e.g., human) administration, it will beunderstood that preparations should meet sterility, pyrogenicity,general safety and purity standards as required by FDA Office ofBiological Standards.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example I Intrathecal Administration of Isoflurane and Sevoflurane

This study was designed to evaluate efficacy of direct intrathecalinjection of anesthetic agent gases in reducing pain and providinganalgesia. The study was conducted over a one (1) month period usinganesthetic gases isoflurane and sevoflurane injected directlyintrathecally or dissolved in saline as shown in the studies below. Thesubject animal used was the rat, since the rat has a well-establishedmodel of pain/analgesia testing. In particular, Sprague-Dawley ratsweighing over 350 gm were used. The rats were anesthetized withpentobarbital (50 mg/kg), and the anesthetic depth of the animals wasdetermined by corneal reflex and paw withdrawal reflex to a noxiousstimulus.

The neck of the rats were shaved and cleaned with disinfectant solutionsin order to avoid bacterial contamination during surgery. A midlinesurgical dissection of the posterior neck muscles was performed toobtain access to the occipito-atlantoid membrane. This membrane wasidentified and then dissected. A sterile polyethylene catheter wasintroduced in the subarachnoid space until the lumbar enlargement of thespinal cord (approximately 7-8 cm measured in each animal). The surgicalwound was closed, first suturing the neck muscles with 3-0 silk suturesand then closing the skin incision with staples.

After the surgery, the rats were moved to their cages and a radiant lampwas placed over the cages so that the rats would not undergoanesthetic-induced hypothermia. The rats were continuously monitoredfrom the end of the surgery until they were fully awake. Rats showingany motor impairment after surgery were euthanized.

On the fifth day after surgery, those rats without wound infection ormotor dysfunction were transported to the pain behavioral lab to enterthe intrathecal study with volatile anesthetics. 12 rats were selectedfor the study. All these rats had intrathecal catheters. Isoflurane(1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) and sevoflurane(fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether) were usedas the halogenated ether compounds. Both of these are halogenatedvolatile anesthetic agents, with isoflurane manufactured by Baxter andsevoflurane manufactured by Abbott Laboratories. The 12 rats weredivided into 3 groups of four rats each for study A and B.

In the first group, 2 microliters of preservative-free normal saline wasinjected via the intrathecal catheter into each rat. This catheter wasthen flushed with preservative-free normal saline. Pain behavioraltesting on this group was then performed.

In the second group, 2 microliters of isoflurane was injected via theintrathecal catheter into each rat. This catheter was also flushed withpreservative-free normal saline. This group was then subjected to painbehavioral testing.

In the third group, 2 microliters of sevoflurane was injected via theintrathecal catheter into each rat. This catheter was also flushed withpreservative-free normal saline. This group was then subjected to painbehavioral testing.

A “hotplate” behavioral test was used to evaluate pain perception andanalgesia. The pain behavioral testing model used in these studies havebeen well established by Tony Yaksh. (See, e.g. Chaplan et al., 1994;Yaksh et al., 2001; Kim and Chung, 1992; Sorkin et al., 2001). This testinvolves determining how quickly a rat will withdraw its hind paw inresponse to a noxious stimulus such as a radiant heat source placeddirectly underneath its paw. This time for withdrawal is known as“thermal withdrawal latency”.

Rats were transferred for testing onto a modified Hargreaves apparatuswith a heated glass plate maintained at 25° C. (see Hargreaves et al.,1988). A focused projection bulb below the plate was aimed at themid-plantar surface of the paw. A photodiode-activated timer measuredthe withdrawal latency, and a cutoff time of 25 seconds was used toprevent tissue damage. Thermal withdrawal latency to radiant heat wasmeasured at 5 minutes and 30 minutes after each intrathecal injection.Each paw was tested three times, and the results were averaged. Thebelow data was collected for both the right and left hind paws:

Group 1: Control Group (Normal Saline) Tested at 5 Minutes

Test 1 Test 2 Test 3 Right Left Right Left Right Left Average Rat 1:9.00 9.26 10.45 6.74 8.42 9.95 8.97 Rat 2: 11.23 9.32 6.34 7.98 10.658.73 7.19 Rat 3: 7.83 8.21 9.67 11.90 8.55 6.38 8.76 Rat 4: 9.72 8.046.77 8.92 7.88 8.95 8.38 Group 1 Average: 8.33 seconds

Group 2 Study A: Isoflurane Group Tested at 5 Minutes

Test 1 Test 2 Test 3 Right Left Right Left Right Left Average Rat 5:19.81 17.23 20.38 18.91 20.34 18.82 19.25 Rat 6: 17.19 19.24 15.88 17.6518.59 20.72 18.21 Rat 7: 19.20 18.11 17.90 19.80 16.71 20.07 18.63 Rat8: 20.31 19.71 18.34 17.18 16.75 16.38 17.95 Group 2 Average: 18.51seconds

Group 3 Study B: Sevoflurane Group Tested at 5 Minutes

Test 1 Test 2 Test 3 Right Left Right Left Right Left Average Rat 9:13.81 14.90 13.23 15.11 16.03 14.83 14.65 Rat 10: 17.19 13.38 14.2912.31 13.75 12.01 13.82 Rat 11: 14.98 12.34 13.93 11.03 12.37 14.1613.14 Rat 12: 10.31 11.83 13.20 12.66 17.59 12.31 12.98 Group 3 Average:13.65 seconds

These rats were then allowed time to recover from their intrathecalinjection. There were no apparent adverse effects such as respiratorydepression, cardiac, or neurological compromise. At 30 minutes after theinjection, the rats were tested again, according to grouping:

Group 1: Control Group (Normal Saline) Tested at 30 Minutes

Test 1 Test 2 Test 3 Right Left Right Left Right Left Average Rat 1:7.32 8.02 9.17 8.64 5.89 7.71 7.79 Rat 2: 6.77 5.98 7.81 6.54 9.03 8.208.59 Rat 3: 7.08 8.39 7.26 8.49 9.23 9.84 8.38 Rat 4: 8.36 9.44 9.159.67 8.54 7.92 8.85 Group 1 Average: 8.40 seconds

Group 2, Study A: Isoflurane Group Tested at 30 Minutes

Test 1 Test 2 Test 3 Right Left Right Left Right Left Average Rat 5:9.87 9.12 10.59 9.02 8.54 9.77 9.48 Rat 6: 9.08 6.35 7.81 8.22 10.4911.62 8.93 Rat 7: 6.32 8.37 9.48 8.45 11.03 10.48 10.52 Rat 8: 9.4110.27 6.76 7.04 7.88 10.32 9.21 Group 2 Average: 9.53 seconds

Group 3, Study B: Sevoflurane Group Tested at 30 Minutes

Test 1 Test 2 Test 3 Right Left Right Left Right Left Average Rat 9:9.23 8.54 7.30 8.29 9.43 8.87 8.61 Rat 10: 7.38 6.87 8.92 7.99 10.838.10 8.35 Rat 11: 10.05 8.44 9.32 11.74 7.66 6.13 8.89 Rat 12: 9.5510.93 8.67 6.68 9.27 12.11 9.54 Group 3 Average: 8.84 seconds

The results of this study demonstrated the efficacy of intrathecaladministration of volatile anesthetic agents in reducing pain. At thesmallest intrathecally delivered dose of 2 microliters, an analgesiceffect of isoflurane and sevoflurane was shown. The thermal latency timewas significantly increased, thus showing that the thermal C-fiber painpathway was effectively dampened. This study also shed some light intothe safety of intrathecally delivering active agent gases. None of therats in the study experienced adverse effects, and all of them fullyrecovered from the intrathecal injection after 30 minutes, as indicatedby the return to thermal latency baseline for all groups.

Example II Preparation of a 5 μL Sample of Isoflurane Dissolved inSaline

Isoflurane was dissolved into saline using the following method (alsoreferred to as the “bubbling” method). Study C: A mock vaporizing devicewas created using a 500 ml modified Erlenmeyer flask (2 inlets and 1catheter into the liquid phase). The flask was partially filled with0.9% normal saline and a stoppered glass pipette was inserted into thebottom of the liquid phase for injection of isoflurane. A second egresspipette allowed egress of gas from the closed container. 2% isofluranesolution in oxygen at 2 L/min was injected through the pipette,saturating the 0.9% saline solution after approximately 10 minutes ofinjection. 5 mL was drawn from the saturated saline solution andadministered to 10 animals using the procedures outlined in Example Iabove.

For study C, all animals were prepared as for experiments A and B. Theinventors injected 4 animals with 5 microliter of dissolved isofluranesolution (as prepared in 0030) via intrathecal catheter. Note, control(baseline) latency to paw withdraw is different in Study C due to adifferent intensity of heat lamp used. Each animal serves as its owncontrol in study C.

Study C Data is presented here: in seconds to paw withdraw to heatsource. Table and graphic format. Results are shown in FIG. 2.

CONTROL 5 MIN 10 MIN 15 MIN 30 MIN 60 MIN RAT 1 4.8 11 5.4 7.6 6.8 6.14.4 15 9 7.3 7.2 5.8 4.8 19.5 9 8.8 4.9 5.1 20 6.8 7 5.2 4.9 RAT 2 3.410.9 9.9 10.4 8.2 3.8 4.3 12.6 8.7 9.4 6.9 4.7 3.6 18.1 12 5.4 8.1 717.3 9 13.4 6.4 4.1 RAT 3 3.6 14.2 12.2 6.1 5.2 4.2 3.8 20 12 7.1 6.13.5 4.7 20 9.1 4.8 5.8 3.3 16 8.9 5.2 6.5 3.8 RAT 5 3.9 9.8 8.8 7.9 4.94.2 2.6 11.8 7.8 6.4 4.3 3.5 2.6 9.1 10.2 6.9 4.7 3.8 11.8 8.1 4.3 3.83.5 mean 3.875 14.81875 9.18125 7.375 5.9375 4.45625 SD 0.7676713.809235 1.77067 2.231171 1.266331 1.073293

Example III Intrathecal Inhibition of Pain Using Isoflurane Dissolved inArtificial Cerebrospinal Fluid

Pain sensitivity was measured after intrathecal administration ofisoflurane in artificial cerebrospinal fluid (ACSF). Further, asdetailed below, the isoflurane was first dissolved in ACSF and thensonicated before administration. The dose response relationship was thenevaluated by generating a stimulus-response (SR) graph in order todetermine relevant concentrations of isoflurane that may be administeredintrathecally to achieve analgesia or anesthesia. The characterizationof the pharmacological profile of intrathecal administration ofisoflurane in ACSF was performed in this example using rats; further, aswould be appreciated by one of skill in the art, analogous approachesmay be used to determine the precise pharmacological profile in humans.

Isoflurane dissolved in ACSF was prepared by the following method.Isoflurane was admixed in a closed vacuum container in a v/v ratio of10-50% with buffered salt solution that approximates cerebrospinal fluid(pH 7.4) with the following composition (in mM): NaCl, 120; KCl, 3;NaHCO₃, 25; CaCl₂, 2.5; MgCl₂, 0.5; glucose, 12. The combined solutionswere mechanically agitated for 3-5 min and then held in a thermo-neutralsonicator until use.

The solutions of isoflurane in ACSF were then administered to ratsintrathecally via the following method. Treatment solution is deliveredvia intrathecal catheter that overlies lumbar segment L1-2 in a volumeof 10 μl followed by a 10 μl flush of ACSF.

Pain perception was tested after intrathecal administration ofisoflurane dissolved in artificial CSF using the “hotplate” behavioraltest, as described above, with the modification that a cutoff time of 20seconds was used. As stated above the “hotplate” behavioral testinvolves testing the hind paw withdrawal threshold to radiant heat(i.e., duration of time between before a rat to lifts a paw away from aheat source).

Intrathecal administration of isoflurane in ACSF resulted in analgesia.As shown in FIG. 3, intrathecal administration of isoflurane in ACSF(i.e., at a 1.46 mg dose of isoflurane) resulted in analgesia asmeasured by testing the hind paw withdrawal threshold to radiant heat. A10 μL solution of isoflurane in ACSF (10% v/v) was used. As describedbelow, this dose of isoflurane represents a moderate dose of intrathecalisoflurane.

The dose response relationship was then evaluated by generating astimulus-response (SR) graph in order to standardize responses acrossanimals and determine relevant concentrations of isoflurane that may beadministered intrathecally to achieve analgesia or anesthesia. FIG. 4shows an stimulus-response (SR) graph of the maximal possible effect(MPE) by dose for the time point of 10 minutes after the injection ofisoflurane in ACSF. Various doses of isoflurane are shown on the x-axis;for example, the 10% v/v solution of isoflurane used above, as shown inFIG. 3, corresponds to approximately a 34% MPE as shown in FIG. 4. MPEis used here to standardize responses across animals. MPE is calculatedas ((drug response time−baseline response time)/(cutoff time−baselineresponse time))*100. The cutoff time used here was 20 seconds. As shownin FIG. 4, a substantial analgesic effect was observed.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions and methods and in the steps or in the sequence of steps ofthe method described herein without departing from the concept, spiritand scope of the invention. More specifically, it will be apparent thatcertain agents which are both chemically and physiologically related maybe substituted for the agents described herein while the same or similarresults would be achieved. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

-   Chaplan et al., J. Neurosci. Methods, 53:55-63, 1994.-   Hargreaves et al., Pain, 32:77-88, 1988.-   Kim and Chung, Pain, 50:355-363, 1992.-   Mathias et al., Revista Brasileira de Anestesiologia, ISSN    0034-7094, 2004.-   Moller et al., Lancet., 351:857-861, 1998.-   Rasmussen et al., Acta Anaesthesiologica Scandinavica,    47(3):260-266, 2003.-   Remington: The Science and Practice of Pharmacy, 20^(th) Ed.,    Baltimore, Md.: Lippincott Williams & Wilkins, 2000-   Rogers et al., BMJ, 321:1-12, 2000.-   Sorkin et al., Anesthesiology, 95:965-973, 2001.-   Yaksh et al., J. Appl. Physiol., 90:2386-2402, 2001.

1. A method for reducing pain in a subject in need of such painreduction comprising parenterally delivering to the subject by a routeother than intravenously a volatile anesthetic dissolved in a solutionin an amount effective to reduce pain.
 2. The method of claim 1, whereinthe anesthetic is delivered locally or regionally.
 3. The method ofclaim 1, wherein the volatile anesthetic is a halogenated etheranesthetic.
 4. The method of claim 1, wherein the anesthetic isdelivered intrathecally, epidurally, or in a nerve block procedure. 5.The method of claim 1, wherein the pain is chronic pain.
 6. The methodof claim 1, wherein the pain is acute pain.
 7. The method of claim 1,wherein the anesthetic is delivered to anesthetize a portion of thesubject prior to a surgery.
 8. The method of claim 1, wherein thevolatile anesthetic is selected from the group consisting of isoflurane,halothane, enflurane, sevoflurane, desflurane, methoxyflurane, andmixtures thereof.
 9. The method of claim 8, wherein the volatileanesthetic is isoflurane.
 10. The method of claim 1, wherein thesolution comprises the anesthetic in an amount ranging from about 5ng/ml to about 100 ng/ml.
 11. The method of claim 1, wherein thesolution comprises from about 5% to about 75% v/v anesthetic insolution.
 12. The method of claim 11, wherein the solution comprisesfrom about 10% to about 50% v/v anesthetic in solution.
 13. The methodof claim 12, wherein the anesthetic is isoflurane.
 14. The method ofclaim 12, wherein the solution is artificial cerebrospinal fluid. 15.The method of claim 12, wherein the solution comprises about 10% v/vanesthetic in solution.
 16. The method of claim 15, wherein theanesthetic is isoflurane and the solution is artificial cerebrospinalfluid.
 17. The method of claim 1, wherein the solution is deliveredepidurally or intrathecally to achieve a dose range of 250 ng/ml to50,000 ng/ml active agent in the spinal fluid.
 18. The method of claim8, wherein the halogenated compound is sevoflurane.
 19. The method ofclaim 1, wherein the delivery of the active agent is continuous.
 20. Themethod of claim 1, wherein the delivery of the active agent is periodic.21. The method of claim 1, wherein the delivery of the active agent is aone-time event.
 22. The method of claim 1, wherein the delivery of theactive agent is both periodically administered and continuouslyadministered to the subject on separate occasions.
 23. The method ofclaim 1, wherein the reduction comprises elimination of pain perceptionof a portion of the body of the subject.
 24. The method of claim 1,wherein the solution comprising the volatile anesthetic is sterile. 25.The method of claim 1, wherein the subject is a human.
 26. The method ofclaim 1, wherein the subject is a mouse or a rat.
 27. The method ofclaim 1, wherein the solution is essentially free of an oil-in-waterlipid emulsion.
 28. The method of claim 1, wherein the solution issaline or artificial cerebrospinal fluid.
 29. The method of claim 28,wherein the saline is normal saline.
 30. A pharmaceutically acceptablecomposition comprising a metered amount of a volatile anestheticdissolved in an aqueous solution; wherein the composition is comprisedin a pharmaceutically acceptable excipient; and wherein the compositionis essentially free of a lipid emulsion.
 31. The composition of claim30, wherein the composition is sterile.
 32. The composition of claim 30,wherein the composition is formulated for intrathecal administration,epidural administration, or administration via a nerve block.
 33. Thecomposition of claim 30, wherein the solution comprises a salinesolution or artificial cerebrospinal fluid.
 34. The composition of claim33, wherein the saline solution is normal saline solution.
 35. Thecomposition of claim 30, wherein the volatile anesthetic is selectedfrom the group consisting of isoflurane, halothane, enflurane,sevoflurane, desflurane, methoxyflurane, and mixtures thereof.
 36. Thecomposition of claim 35, wherein the volatile anesthetic is isoflurane.37. The composition of claim 35, wherein the volatile anesthetic isdissolved in the aqueous solution at a concentration of from about 10%to about 50% v/v.
 38. The composition of claim 37, wherein the volatileanesthetic is dissolved in the aqueous solution at a concentration ofabout 10% v/v.
 39. The composition of claim 37, wherein the volatileanesthetic is isoflurane and the aqueous solution is artificialcerebrospinal fluid.
 40. A sealed container comprising the anestheticsolution of any one of claim
 30. 41. The sealed container of claim 40,wherein the interior of the container is sterile.
 42. The sealedcontainer of claim 41, wherein the container comprises a rubber stopperwhich may be easily pierced by an injection needle.
 43. The sealedcontainer of claim 41, wherein the container comprises the chamberportion of a syringe.
 44. The container of claim 41, wherein thecontainer comprises a drip chamber.
 45. The container of claim 44,wherein the drip chamber is coupled to a catheter.
 46. The container ofclaim 45, wherein the catheter is an epidural catheter or an intrathecalcatheter.
 47. The container of claim 41, wherein the container is aplastic bag, a glass bottle, or a plastic bottle.
 48. The container ofclaim 41, wherein the container is coupled to an infusion pump.
 49. Thecontainer of claim 48, wherein the infusion pump is an intrathecal pump,an epidural delivery infusion pump, or a patient control analgesia (PCA)pump.
 50. The container of claim 48, wherein the infusion pump isprogrammable.